Irene Riera-Tur

Hikma Pharmaceuticals (Germany)

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Irina Dudanova

Max Planck Institute of Neurobiology

Victoria A. Trinkaus

Max Planck Institute of Biochemistry

F. Ulrich Hartl

Max Planck Institute of Biochemistry

Wolfgang Baumeister

Max Planck Institute of Biochemistry

Rubén Fernández‐Busnadiego

University of Göttingen

Mark S. Hipp

University Medical Center Groningen

Thomas Arzberger

Ludwig-Maximilians-Universität München

Rahmi Imamoglu

Max Planck Institute of Biochemistry

Felix J.B. Bäuerlein

University of Göttingen

Patricia Yuste‐Checa

Max Planck Institute of Biochemistry

Cooperative Institutions

Max Planck Institute of Biochemistry

Max Planck Institute of Neurobiology

Hikma Pharmaceuticals (Germany)

Max Planck Society

University Medical Center Groningen

University of Groningen

Munich Cluster for Systems Neurology

Carl von Ossietzky Universität Oldenburg

Technical University of Munich

University of Göttingen

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The extracellular chaperone Clusterin enhances Tau aggregate seeding in a cellular model

Nature Communications (2021)

Patricia Yuste‐Checa Victoria A. Trinkaus Irene Riera-Tur Rahmi Imamoglu Theresa Schaller

Abstract Spreading of aggregate pathology across brain regions acts as a driver of disease progression in Tau-related neurodegeneration, including Alzheimer’s disease (AD) and frontotemporal dementia. Aggregate seeds released from affected cells are internalized by naïve cells and induce the prion-like templating of soluble Tau into neurotoxic aggregates. Here we show in a cellular model system and in neurons that Clusterin, an abundant extracellular chaperone, strongly enhances Tau aggregate seeding. Upon interaction with Tau aggregates, Clusterin stabilizes highly potent, soluble seed species. Tau/Clusterin complexes enter recipient cells via endocytosis and compromise the endolysosomal compartment, allowing transfer to the cytosol where they propagate aggregation of endogenous Tau. Thus, upregulation of Clusterin, as observed in AD patients, may enhance Tau seeding and possibly accelerate the spreading of Tau pathology.

Clusterin

Chaperone (clinical)

Cellular model

10.1038/s41467-021-25060-1

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Citations (46)

In situarchitecture of neuronal α-Synuclein inclusions

bioRxiv (Cold Spring Harbor Laboratory) (2020)

Victoria A. Trinkaus Irene Riera-Tur Antonio Martínez-Sánchez Felix J.B. Bäuerlein Qiang Guo

Summary α-Synuclein (α-Syn) aggregation is a hallmark of devastating neurodegenerative disorders including Parkinson’s disease (PD) and multiple systems atrophy (MSA) 1,2 . α-Syn aggregates spread throughout the brain during disease progression 2 , suggesting mechanisms of intercellular seeding. Formation of α-Syn amyloid fibrils is observed in vitro 3,4 and fibrillar α-Syn has been purified from patient brains 5,6 , but recent reports questioned whether disease-relevant α-Syn aggregates are fibrillar in structure 7-9 . Here we use cryo-electron tomography (cryo-ET) to image neuronal Lewy body-like α-Syn inclusions in situ at molecular resolution. We show that the inclusions consist of α-Syn fibrils crisscrossing a variety of cellular organelles such as the endoplasmic reticulum (ER), mitochondria and autophagic structures, without interacting with membranes directly. Neuronal inclusions seeded by recombinant or MSA patient-derived α-Syn aggregates have overall similar architecture, although MSA-seeded fibrils show higher structural flexibility. Using gold-labeled seeds we find that aggregate nucleation is predominantly mediated by α-Syn oligomers, with fibrils growing unidirectionally from the seed. Our results conclusively demonstrate that neuronal α-Syn inclusions contain α-Syn fibrils intermixed with cellular membranes, and illuminate the mechanism of aggregate nucleation.

Amyloid (mycology)

Organelle

10.1101/2020.08.07.234138

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Citations (1)

Characterization of the TLR9-Activating Potential of LNA-Modified Antisense Oligonucleotides

Nucleic Acid Therapeutics (2024)

Irene Riera-Tur Julia Hinterdobler André Maaske Anne Sadewasser Monika Schell

Early characterization of the immunostimulatory potential of therapeutic antisense oligonucleotides (ASOs) is crucial. At present, little is known about the toll-like receptor 9 (TLR9)-mediated immunostimulatory potential of third-generation locked nucleic acid (LNA)-modified ASOs. In this study, we have systematically investigated the TLR9-activating potential of LNA-modified oligonucleotides using different mouse and human cell culture systems. Although it has been reported that LNA modifications as well as cytosine methylation of 5'-cytosine-phosphate-guanine-3' (CpG) motifs can reduce TLR9 stimulation by phosphorothioate (PTO)-modified oligonucleotides, we identified CpG-containing LNA gapmers with substantial TLR9-stimulatory activity. We further identified immunostimulatory LNA gapmers without CpG motifs. Unexpectedly, methylation of cytosines only within the CpG motif did not necessarily reduce but could even increase TLR9 activation. In contrast, systematic methylation of all cytosines reduced or even abrogated TLR9 activation in most cases. Context dependently, the introduction of LNA-modifications into the flanks could either increase or decrease TLR9 stimulation. Overall, our results indicate that TLR9-dependent immunostimulatory potential is an individual feature of an oligonucleotide and needs to be investigated on a case-by-case basis.

TLR9

10.1089/nat.2024.0013

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Amyloid-like aggregating proteins cause lysosomal defects in neurons via gain-of-function toxicity

Life Science Alliance (2021)

Irene Riera-Tur Tillman Schäfer Daniel Hornburg Archana Mishra Miguel da Silva Padilha

The autophagy-lysosomal pathway is impaired in many neurodegenerative diseases characterized by protein aggregation, but the link between aggregation and lysosomal dysfunction remains poorly understood. Here, we combine cryo-electron tomography, proteomics, and cell biology studies to investigate the effects of protein aggregates in primary neurons. We use artificial amyloid-like β-sheet proteins (β proteins) to focus on the gain-of-function aspect of aggregation. These proteins form fibrillar aggregates and cause neurotoxicity. We show that late stages of autophagy are impaired by the aggregates, resulting in lysosomal alterations reminiscent of lysosomal storage disorders. Mechanistically, β proteins interact with and sequester AP-3 μ1, a subunit of the AP-3 adaptor complex involved in protein trafficking to lysosomal organelles. This leads to destabilization of the AP-3 complex, missorting of AP-3 cargo, and lysosomal defects. Restoring AP-3μ1 expression ameliorates neurotoxicity caused by β proteins. Altogether, our results highlight the link between protein aggregation, lysosomal impairments, and neurotoxicity.

Neurotoxicity

Amyloid (mycology)

Organelle

10.26508/lsa.202101185

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Citations (18)

The extracellular chaperone Clusterin enhances Tau aggregate seeding in a cellular model

bioRxiv (Cold Spring Harbor Laboratory) (2021)

Patricia Yuste‐Checa Victoria A. Trinkaus Irene Riera-Tur Rahmi Imamoglu Theresa Schaller

Clusterin

Chaperone (clinical)

Cellular model

10.1101/2021.07.16.452659

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Citations (1)

In situ architecture of neuronal α-Synuclein inclusions

Nature Communications (2021)

Victoria A. Trinkaus Irene Riera-Tur Antonio Martínez-Sánchez Felix J.B. Bäuerlein Qiang Guo

Abstract The molecular architecture of α-Synuclein (α-Syn) inclusions, pathognomonic of various neurodegenerative disorders, remains unclear. α-Syn inclusions were long thought to consist mainly of α-Syn fibrils, but recent reports pointed to intracellular membranes as the major inclusion component. Here, we use cryo-electron tomography (cryo-ET) to image neuronal α-Syn inclusions in situ at molecular resolution. We show that inclusions seeded by α-Syn aggregates produced recombinantly or purified from patient brain consist of α-Syn fibrils crisscrossing a variety of cellular organelles. Using gold-labeled seeds, we find that aggregate seeding is predominantly mediated by small α-Syn fibrils, from which cytoplasmic fibrils grow unidirectionally. Detailed analysis of membrane interactions revealed that α-Syn fibrils do not contact membranes directly, and that α-Syn does not drive membrane clustering. Altogether, we conclusively demonstrate that neuronal α-Syn inclusions consist of α-Syn fibrils intermixed with membranous organelles, and illuminate the mechanism of aggregate seeding and cellular interaction.

Organelle

Cytoplasmic inclusion

Pathognomonic

10.1038/s41467-021-22108-0

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Citations (95)

Amyloid-like aggregates cause lysosomal defects in neurons via gain-of-function toxicity

bioRxiv (Cold Spring Harbor Laboratory) (2019)

Irene Riera-Tur Tillman Schäfer Daniel Hornburg Archana Mishra Lorena Fernández-Mosquera

Abstract The autophagy-lysosomal pathway is impaired in many neurodegenerative diseases characterized by protein aggregation, but the link between aggregation and lysosomal dysfunction remains poorly understood. Here, we combine cryo-electron tomography, proteomics and cell biology studies to investigate the effects of protein aggregates in primary neurons. We use artificial amyloid-like β-sheet proteins (β proteins) to focus on the gain-of-function aspect of aggregation. These proteins form fibrillar aggregates and cause neurotoxicity. We show that late stages of autophagy are impaired by the aggregates, resulting in lysosomal alterations reminiscent of lysosomal storage disorders. Mechanistically, β proteins interact with and sequester AP-3μ1, a subunit of the AP-3 adaptor complex involved in protein trafficking to lysosomal organelles. This leads to destabilization of the AP-3 complex, missorting of AP-3 cargo, and lysosomal defects. Restoring AP-3μ1 expression ameliorates neurotoxicity caused by β proteins. Altogether, our results highlight the link between protein aggregation and neurotoxicity, pointing to lysosomes as particularly vulnerable organelles.

Neurotoxicity

Organelle

Amyloid (mycology)

10.1101/2019.12.16.877431

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Citations (7)